At a glance: The TRAILBLAZER trials

Donanemab, a monoclonal antibody, is being investigated in the TRAILBLAZER trials for the treatment of Alzheimer’s disease (AD). Donanemab targets deposited amyloid plaques to reduce the existing amyloid burden from the brain. Here we outline the seven trials focusing on early symptomatic AD, with top-line results outlined where possible as most trials are yet to complete or publish findings. All trials are phase 3, except ALZ and EXT, which are phase 2. Inclusion criteria are similar across studies, targeting participants with detectable cognitive decline but not advanced disease, and ALZ 3 is targeting cognitively normal people at high risk for AD. All trials aim to evaluate the safety, tolerability, and efficacy of the drug administered intravenously. One trial (ALZ 4) compared donanemab with another treatment (aducanumab), while another (ALZ 6) is investigating different dosing regimens. Some trials also have additional goals, such as validating video scale assessments (in EXT) or investigating the effect on the frequency and severity of ARIA-E (in ALZ 6). Specific inclusion criteria, objectives, and the design of each trial are in the tables below. The drug manufacturer Eli Lilly is the sponsor of all trials. 2024 Springer Medizin Verlag GmbH × View acronyms TRAILBLAZER-ALZ TRAILBLAZER-ALZ Completed, published Trial population Early symptomatic AD (prodromal AD, defined as symptomatic predementia phase in which mild cognitive impairment is apparent, or diagnosis of mild AD with dementia), gradual and progressive change in memory function for ≥6 months, presence of brain tau pathology on PET scan (but below an upper threshold), and MMSE score of 20–28 Intervention and comparator Donanemab 700 mg for first three doses and 1400 mg thereafter vs placebo every 4 weeks for up to 72 weeks Primary outcomes –6.86 vs –10.06 change in iADRS score from baseline to 76 weeks (p=0.04) Secondary outcomes No significant difference between groups in most outcomes (CDR-SB, ADAS-Cog13, ADCS-iADL, and MMSE scores, global tau load on PET scan, and hippocampal volume) from baseline to 76 weeks –84.13 vs 0.93 CL change in amyloid plaque level on PET scan from baseline to 76 weeks; amyloid-negative status* achieved in 68% of donanemab-treated patients at 76 weeks Greater decrease in whole-brain volume and increase in ventricular volume with donanemab vs placebo from baseline to 76 weeks Adverse events Incidence of ARIA-E significantly higher with donanemab vs placebo (p<0.001) NCT03367403 Trial results: N Engl J Med 2021; 384: 1691–1704 Exploratory post-hoc analysis: JAMA Neurol 2022; 79: 1015–1024 *Amyloid plaque level of <24.1 CL (complete amyloid clearance). View acronyms TRAILBLAZER-EXT TRAILBLAZER-EXT Completed, not published Trial population Early symptomatic AD Had participated in a double-blind treatment period of a sponsor-approved donanemab trial (eg, TRAILBLAZER-ALZ) Intervention and comparator Part A: no intervention; cognitive and functional scale assessments for 1 month Part B: donanemab for up to 72 weeks vs baseline Primary outcomes Part A: correlation between VTC and on-site assessment of ADAS-Cog13, ADCS-ADL, MMSE, and CDR-SB scores at 1 month Part B: percentage of participants with one or more AE or serious AE up to 72 weeks Secondary outcomes Clinical changes (MMSE, ADAS-Cog13, iADRS, ADCS-iADL, and CDR-SB scores, amyloid plaque deposition on PET scan, brain volume, and C-SSRS score), pharmacokinetics, and anti-donanemab antibodies from baseline to 72 weeks NCT04640077 No publications to date View acronyms TRAILBLAZER-ALZ 2 TRAILBLAZER-ALZ 2 Active (not recruiting), published Trial population Early symptomatic AD (mild cognitive impairment or AD with mild dementia), gradual and progressive change in memory function for ≥6 months, presence of brain amyloid and tau pathology on PET scan, and MMSE score of 20–28 Intervention and comparator Donanemab 700 mg for first three doses and 1400 mg thereafter vs placebo every 4 weeks for up to 72 weeks, followed by a 78-week extension period Primary outcomes Change in iADRS score from baseline to 76 weeks: –10.19 vs –13.11 in overall population (p<0.001) –6.02 vs –9.27 in low-medium tau population (p<0.001) Secondary outcomes Significantly smaller change in most outcomes (CDR-SB, ADCS-iADL, and ADAS-Cog13 scores) with donanemab vs placebo from baseline to 76 weeks Change in amyloid plaque level on PET scan from baseline to 76 weeks: –87.0 vs 0.67 CL in overall population, and –88.0 vs 0.2 CL in low-medium tau population No significant difference between groups in MMSE score and tau deposition on PET scan Amyloid clearance* achieved in 76% of donanemab-treated patients in overall population and 80% in low-medium tau population at 76 weeks Greater decrease in whole-brain volume and increase in ventricular volume, and lesser decrease in hippocampal volume, with donanemab vs placebo from baseline to 76 weeks Adverse events More frequent with donanemab vs placebo NCT04437511 Trial results: JAMA 2023; 330: 512–527 *Amyloid plaque level of <24.1 CL (complete amyloid clearance). View acronyms TRAILBLAZER-ALZ 3 TRAILBLAZER-ALZ 3 Recruiting Trial population Preclinical AD: phosphorylated tau result consistent with the presence of amyloid and early-tau pathology, but TICS-M score indicates intact cognitive functioning; excludes mild cognitive impairment or dementia Intervention and comparator Donanemab vs placebo for up to 182 weeks Primary outcomes Time to clinical progression (CDR-GS) up to 182 weeks Secondary outcomes Clinical changes (ISLT, CPAL, iDSSTm, category fluency, FNAME, BPS-O, CBB, CFI, and MoCA scores from baseline to 182 weeks, CDR-SB score up to 32 weeks), pharmacokinetics up to 76 weeks, and percentage of participants with ADAs up to 16 weeks NCT05026866 No publications to date View acronyms TRAILBLAZER-ALZ 4 TRAILBLAZER-ALZ 4 Completed, not published Trial population Early symptomatic AD, gradual and progressive change in memory function for ≥6 months, CDR-GS of 0.5 or 1, presence of brain amyloid pathology on PET scan, and MMSE score of 20–30 Intervention and comparator Donanemab 700 mg for first three doses and 1400 mg thereafter every 4 weeks vs aducanumab (per US label) Primary outcomes Percentage of participants who achieve amyloid plaque clearance* on PET scan at 6 months in overall population or in low-medium tau population Secondary outcomes Change in amyloid plaque level from baseline to 6 months in overall population or in low-medium tau population NCT05108922 No publications to date *Amyloid plaque level of <24.1 CL (complete amyloid clearance). View acronyms TRAILBLAZER-ALZ 5 TRAILBLAZER-ALZ 5 Recruiting Trial population Early symptomatic AD, gradual and progressive change in memory function for ≥6 months, presence of brain amyloid and tau pathology on PET scan, and MMSE score of 20–28 Intervention and comparator Donanemab vs placebo Primary outcomes Change in iADRS score from baseline to 76 weeks in overall population or in low-medium tau population Secondary outcomes Change in MMSE, ADAS-Cog13, CDR-SB, ADCS-iADL, QOL-AD, RUD-Lite, and NPI scores, amyloid plaque deposition on PET scan, pharmacokinetics, and number of patients with ADAs from baseline to 76 weeks NCT05508789 No publications to date View acronyms TRAILBLAZER-ALZ 6 TRAILBLAZER‑ALZ 6 Recruiting Trial population Early symptomatic AD, gradual and progressive change in memory function for ≥6 months, presence of brain amyloid pathology on PET scan, and MMSE score of 20–28 Intervention and comparator Donanemab administered at four differing dose levels vs placebo Primary outcomes Percentage of participants with any occurrence of ARIA-E up to 24 weeks Secondary outcomes Percentage of participants with any occurrence of ARIA-E at 52 weeks, change in amyloid plaque deposition on PET scan from baseline to 76 weeks, percentage of participants with any occurrence of ARIA-H at 24 and 52 weeks, percentage of participants with maximum severity of ARIA-E or ARIA-H at 52 weeks, pharmacokinetics up to 52 weeks, and number of participants with ADAs up to 91 weeks NCT05738486 No publications to date View acronyms Acronyms AD=Alzheimer’s disease; ADA=Anti-Drug Antibody; ADAS-Cog13=Alzheimer's Disease Assessment Scale - Cognitive Subscale; ADCS-ADL=Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory; ADCS-iADL=Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living Inventory; AE=adverse event; ARIA-E=Amyloid-Related Imaging Abnormality - Edema/Effusion; ARIA-H=Amyloid-Related Imaging Abnormality - Hemorrhage/Hemosiderin Deposits; BPS-O=Behavioral Pattern Separation - Object test; CBB=Cogstate Brief Battery; CDR-GS=Clinical Dementia Rating - Global Score; CDR-SB=Clinical Dementia Rating - Sum of Boxes; CFI=Cognitive Function Index; CL=centiloid; CPAL=Continuous Paired Associate Learning; C-SSRS=Columbia - Suicide Severity Rating Scale; FNAME=Face Name Association Test; iADRS=Integrated Alzheimer's Disease Rating Scale; iDSSTm=International Daily Symbol Substitution Test - Medicines; ISLT=International Shopping List Test; MMSE=Mini Mental State Examination; MoCA=Montreal Cognitive Assessment; NPI=Neuropsychiatric Inventory; PET=positron emission tomography; QOL-AD=Quality of Life in Alzheimer's Disease; RUD-Lite=Resource Utilization in Dementia - Lite Version; TICS-M=Telephone Interview for Cognitive Status - Modified; VTC=video teleconference. 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